IL-6 is a cytokine called B-cell stimulating factor 2 (BSF2) or interferon β2. IL-6 was discovered as a differentiation factor involved in the activation of B-cell lymphocytes (Non-Patent Document 1), and was later revealed to be a multifunctional cytokine that influences the function of various cells (Non-Patent Document 2). IL-6 has been reported to induce maturation of T lymphocyte cells (Non-Patent Document 3).
IL-6 transmits its biological activity via two kinds of proteins on the cell. The first kind of protein is the IL-6 receptor, which is a ligand binding protein to which IL-6 binds; it has a molecular weight of about 80 kDa (Non-Patent Documents 4 and 5). The IL-6 receptor is present in a membrane-bound form that penetrates and is expressed on the cell membrane, and also as a soluble IL-6 receptor, which mainly consists of the extracellular region of the membrane-bound form.
The other kind of protein is the membrane protein gp130, which has a molecular weight of about 130 kDa and is involved in non-ligand binding signal transduction. The biological activity of IL-6 is transmitted into the cell through formation of an IL-6/IL-6 receptor complex by IL-6 and 11-6 receptor followed by binding of the complex with gp130 (Non-Patent Document 6).
IL-6 inhibitors are substances that inhibit the transmission of IL-6 biological activity. Currently, known IL-6 inhibitors include antibodies against IL-6 (anti-IL-6 antibodies), antibodies against IL-6 receptor (anti-IL-6 receptor antibodies), antibodies against gp 130 (anti-gp130 antibodies), IL-6 variants, partial peptides of IL-6 or IL-6 receptor, and such.
There are several reports regarding anti-IL-6 receptor antibodies (Non-Patent Documents 7 and 8; and Patent Documents 1-3). One such report details a humanized PM-1 antibody, which is obtained by transplanting the complementarity determining region (CDR) of mouse antibody PM-1 (Non-Patent Document 9), which is an anti-IL-6 receptor antibody, into a human antibody (Patent Document 4).
IL-6 is known to serve as a killer cell helper factor (KHF) involved in the induction of cytotoxic T cells (Non-Patent Document 10). In-vitro experiments using human rIL-6 show that in the presence of IL-2, rIL-6 induces the differentiation of cytotoxic T cells from human peripheral blood T cells and CD4-/CD8- or CD4-/CD8+ thymus T cells. IL-6 is also known to function in vivo as a cytotoxic T cell differentiation-inducing factor (Non-Patent Document 11).
However, various other cytokines in addition to IL-6 are also known to function as KHFs in vivo, and to date there have been no reports clarifying whether or not IL-6 inhibitors can suppress the induction of cytotoxic T cells in vivo.
The prior-art documents related to the present invention are shown below.    Non-Patent Document 1: Hirano, T. et al., Nature (1986) 324, 73-76    Non-Patent Document 2: Akira, S. et al., Adv. in Immunology (1993) 54, 1-78    Non-Patent Document 3: Lotz, M. et al., J. Exp. Med. (1988) 167, 1253-1258    Non-Patent Document 4: Taga, T. et al., J. Exp. Med. (1987) 166, 967-981    Non-Patent Document 5: Yamasaki, K. et al., Science (1988) 241, 825-828    Non-Patent Document 6: Taga, T. et al., Cell (1989) 58, 573-581    Non-Patent Document 7: Novick, D. et al., Hybridoma (1991) 10, 137-146    Non-Patent Document 8: Huang, Y. W. et al., Hybridoma (1993) 12, 621-630    Non-Patent Document 9: Hirata, Y. et al., J. Immunol. (1989) 143, 2900-2906    Non-Patent Document 10: Okada M. et al., J. Immunology 141:1543-1549, 1988    Non-Patent Document 11: Kitahara M. et al, Jpn. J. Cancer Res. 81:1032-1038.1990    Patent Document 1: WO 95/09873    Patent Document 2: French Patent Application No. FR 2694767    Patent Document 3: U.S. Pat. No. 5,216,128    Patent Document 4: WO 92/19759